Method for the treatment of urinary incontinence

ABSTRACT

Urinary incontinence is alleviated in a mammal by administering to the mammal a urinary incontinence alleviating amount of dextromethorphan, dextrorphan, their mixtures and/or pharmaceutically acceptable salts, alone or in combination with a pharmacologically active agent such as an anticholinergic, sympathomimetic, tricyclic antidepressant, antispasmodic, direct-acting smooth muscle relaxant, estrogen, compound having estrogen-like activity, or any combination of the foregoing.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.08/734,738 filed Oct. 21, 1996 now U.S. Pat. No. 6,562,835 which, inturn, is a divisional of U.S. application Ser. No. 08/398,389 filed Mar.3, 1995, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for treating urinaryincontinence.

2. Description of Related Art

Urinary incontinence is a fairly common medical problem in which urineis involuntarily lost. Urinary incontinence may be transient orpersistent. Common causes of transient urinary incontinence includeinfection, atrophic urethritis, administration of diuretics anddelirium. Persistent urinary incontinence is classified into four types:(1) stress incontinence which involves involuntary loss of urine duringcoughing, sneezing, laughing, or other physical activity; (2) urgeincontinence which involves involuntary loss of urine associated with anabrupt or strong desire to void; (3) overflow incontinence whichinvolves involuntary loss of urine associated with over-distension ofthe bladder; and (4) mixed incontinence which involves a combination ofat least two of the above types.

Persistent urinary incontinence can result from spastic or hyperactivebladder smooth muscle such as detrusor originating incontinence. Incertain instances such incontinence is caused by loss of controlresulting from spinal injury, parkinsonism, multiple sclerosis orrecurrent bladder infection to name a few. Treatment of incontinence mayinvolve surgery or administration of any of various pharmacologicalagents, e.g., a anticholinergic such as oxybutynin, atropine,propantheline, terodiline, dicyclomine and others, a sympathomimeticsuch as ephedrine, pseudoephedrine, phenylpropanolamine and others, atricyclic antidepressant such as amitriptyline, imipramine, doxepin andothers, an estrogen or a direct acting antispasmodic such as flavoxate.In addition to treating incontinence, such pharmacological agents maycause other powerful physiologic responses such as excitability(sympathomimetics), and dry mouth, drowsiness, dizziness orhallucinations (anticholinergics or tricyclic antidepressants).

Other compounds described as useful for treating urinary incontinenceare described, e.g., in U.S. Pat. Nos. 4,645,758, 4,865,843, 5,080,905,5,236,956, 5,233,053, 5,252,589, 5,258,390, 5,272,163, 5,340,805,5,340,819, 5,340,826, and 5,266,596. U.S. Pat. No. 5,192,751 describesthe use of certain competitive N-methyl-D-aspartate (NMDA) receptorantagonists in the treatment of urinary incontinence. It is notedtherein that a non-competitive NMDA receptor antagonist, MK-801, hasbeen reported to produce an increase in frequency in micturition (Veraet al., Neurosci. Lett., 134, 135-138 (1991)).

Dextromethorphan and its main metabolite, dextrorphan, arenon-competitive NMDA receptor antagonists having few, if any, sideeffects at indicated dosage levels. Dextromethorphan and dextrorphanhave been used as antitussives, for treatment of chronic pain (U.S. Pat.No. 5,352,683) and for inhibiting the development of tolerance to and/ordependence on a narcotic analgesic (U.S. Pat. No. 5,321,012).Surprisingly, it has now been found that the non-competitive NMDAreceptor antagonists dextromethorphan and dextrorphan are useful in thetreatment of urinary incontinence.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a method forthe treatment of urinary incontinence which comprises administering to amammal exhibiting urinary incontinence a urinary incontinencealleviating amount of at least one morphinan selected from the groupconsisting of dextromethorphan, dextrorphan and pharmaceuticallyacceptable salts thereof. The method can optionally includeadministration of one or more pharmacologically active agents selectedfrom the group consisting of anticholinergics, sympathomimetics,tricyclic antidepressants, antispasmodics, direct acting bladder smoothmuscle relaxants, estrogens, compounds having estrogen-like activity,and any combination of the foregoing.

In another embodiment of the present invention, there is provided amethod of decreasing micturition frequency in a mammal which comprisesadministering to a mammal a micturition decreasing amount of at leastone morphinan selected from the group consisting of dextromethorphan,dextrorphan and pharmaceutically acceptable salts thereof. The methodcan optionally include administration of any of the pharmacologicallyactive agents mentioned above.

BRIEF DESCRIPTION OF THE DRAWINGS

In the accompanying drawings:

FIG. 1 is a graphical representation of test results showing therapeuticeffects of intravenous administration of dextromethorphan on absolutemicturition pressures in rats; and,

FIG. 2 is a graphical representation of test results showing therapeuticeffects of intravenous administration of dextromethorphan on micturitionfrequency in rats.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Dextromethorphan ((+)-3-methoxy-N-methylmorphinan) and dextrorphan((+)-3-hydroxy-N-methylmorphinan), their mixtures and pharmaceuticallyacceptable salts are utilized in accordance with the method of thepresent invention. Accordingly, dextromethorphan, dextrorphan, theirmixtures and/or pharmaceutically acceptable salts are administered byany known route of administration for the relief of symptoms of bladderinstability associated with voiding in patients with uninhibitedneurogenic or reflex neurogenic bladder such as urgency, frequency,urine leakage, urge incontinence, stress incontinence, overflowincontinence, mixed incontinence or dysuria. Dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable salts arealso useful in the treatment of interstitial cystitis, a chronicinflammatory condition of unknown etiology resulting in reduced bladdercapacity and severe bladder irritative symptoms. Administration ofdextromethorphan, dextrorphan, their mixtures and/or pharmaceuticallyacceptable salts acts to quiet the bladder and reduce the frequency ofmicturition.

Administration of dextromethorphan, dextrorphan their mixtures and/orpharmaceutically acceptable salts can be orally or transdermally or byintravenous, intramuscular, subcutaneous, intrathecal, epidural orintracerebro-ventricular injection. Effective dosage levels can varywidely, e.g., from about 0.25 to about 250 mg/day, but actual amountswill, of course, depend on the state and circumstances of the patientbeing treated. As those skilled in the art recognize, many factors thatmodify the action of the active substance herein will be taken intoaccount by the treating physician such as the age, body weight, sex,diet and condition of the patient, the time of administration, the rateand route of administration, and so forth. Optimal dosages for a givenset of conditions can be ascertained by those skilled in the art usingconventional dosage determination tests in view of the experimental dataprovided herein.

Therapeutic compositions containing dextromethorphan, dextrorphan, theirmixtures and/or pharmaceutically acceptable salts will ordinarily beformulated with one or more pharmaceutically acceptable ingredients inaccordance with known and established practice. Thus, dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable salts canbe formulated as a liquid, powder, elixir, injectable solution, etc.Formulations for oral use can be provided as hard gelatin capsuleswherein dextromethorphan, dextrorphan, their mixtures and/orpharmaceutically acceptable salts are mixed with an inert solid diluentsuch as calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein dextromethorphan, dextrorphan, their mixturesand/or pharmaceutically acceptable salts are mixed with an oleaginousmedium, e.g., liquid paraffin or olive oil.

Aqueous suspensions can contain the dextromethorphan, dextrorphan, theirmixtures and/or pharmaceutically acceptable salts in admixture withpharmaceutically acceptable excipients such as suspending agents, e.g.,sodium carboxymethyl cellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia; dispersing or wetting agents such asnaturally occurring phosphatide, e.g., lecithin, or condensationproducts of an alkaline oxide with fatty acids, e.g., polyoxyethylenestearate, or condensation products of ethylene oxide with long chainaliphatic alcohols, e.g. heptadecaethylene-oxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol, e.g., polyoxyethylene sorbitol monoleate or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, e.g., polyoxyethylene sorbitan monoleate. Suchaqueous suspensions can also contain one or more preservatives, e.g.,ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, saccharin or sodium or calcium cyclamate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable salts inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, e.g., sweetening, flavoring and coloring agents,can also be present. Syrups and elixirs can be formulated withsweetening agents, for example glycerol, sorbitol or sucrose. Suchformulations can also contain a demulcent, a preservative and flavoringand coloring agents.

Dextromethorphan, dextrorphan, their mixtures and/or pharmaceuticallyacceptable salts are advantageously provided in sustained release dosageform of which many kinds are known, e.g., as described in U.S. Pat. Nos.4,788,055; 4,816,264; 4,828,836; 4,834,965; 4,834,985; 4,996,047;5,071,646; and, 5,133,974, the contents of which are incorporated byreference herein.

It is also within the scope of this invention to administerdextromethorphan, dextrorphan, their mixtures and/or pharmaceuticallyacceptable salts prior to, concurrently with, or after administration ofany other known pharmacologically active agent useful for treatingurinary incontinence. Such agents include, but are not limited to,anticholinergics such as oxybutynin, atropine, propantheline,terodiline, dicyclomine, etc., sympathomimetics such as ephedrine,pseudoephedrine, epinephrine, phenylpropanolamine, etc., tricyclicantidepressants such as imipramine, doxepin, amitriptyline, etc.,estrogens or estrogen-related compounds having estrogen-like activitysuch as estradiol, estrone, etc., and antispasmodics or direct actingbladder smooth muscle relaxants such as flavoxate. For a detaileddiscussion of these pharmacologically active agents, reference may bemade to “Goodman and Gillman's Pharmacological Basis of Therapeutics”,Goodman et al., eds. 7th ed., 1985, Macmillan and Company, New York.

The examples that follow are illustrative of the present invention andshould not be construed as limiting.

EXAMPLE 1

Ten female Sprague-Dawley rats having a mean weight of 263±19 g wereanesthetized with urethane (1.2 g/k, sc.). A midline incision wasperformed to expose the bladder and a 23G catheter was inserted into thebladder dome for the measurement of intravesical pressure. A non-stoptransvesical cystometrogram, as described in J. Pharmacological.Methods, 15, pp. 157-167 (1986), was used, at a filling rate of 0.216ml/min. of saline, to access the filling and voiding characteristics ofthe bladder. Through the continuous cystometry method thus afforded,consecutive micturition could be recorded. Dextromethorphan was given atintravenous does of: 1.0, 3.0, 10, 30, 50 mg/kg after the initialbaseline micturition sequence was reliably measured for approximately 12min. From these recordings the absolute values in maximum pressureobtained and the frequency of micturition was measured. A dose responsecurve illustrating the effect of dextromethorphan on the absolutemicturition pressures in the range of 1-50 mg/kg is given in FIG. 1.Data given are mean and SE.

The volume evoked micturition reflex was suppressed in a dose sensitivemanner as seen from the effect of increasing doses of dextromethorphanon the cystometrogram. In particular it was found that at doses in therange of 10-30 mg/kg, the volume evoked micturition contractions arealmost totally suppressed. A significant sustained reduction in detrusorpressure is produced at a dose level of 3 mg/kg and a 50% reduction isevident at 10 mg/kg. As shown in FIG. 1, at higher doses ofdextromethorphan, the rate of decrease in detrusor pressure isdiminished. Furthermore at does higher than 10 mg/kg the effect of thedrug appears to be bimodal, producing an initial increase in detrusorpressure before suppression.

The corresponding dose response effect of dextromethorphan on thefrequency of micturition is given in FIG. 2. As shown, the frequency ofmicturition decrements gradually with respect to dose when compared tothe pressure.

EXAMPLE 2

A capsule containing dextromethorphan hydrobromide contains thefollowing ingredients:

Ingredient mg/Capsule Dextromethorphan Hydrobromide USP 20Pregelatinized Starch NF 50 Colloidal Silicon Dioxide 1.5

EXAMPLE 3

A tablet containing dextromethorphan hydrobromide contains the followingingredients:

Ingredient mg/Tablet Dextromethorphan Hydrobromide USP 20Microcrystalline Cellulose NF 17 Lactose NF anhydrous 68 CroscarmelloseNF 1 Colloidal Silicon Dioxide 1.5 Magnesium Stearate NF 1.5

EXAMPLE 4

A controlled release tablet containing dextromethorphan hydrobromidecontains the following ingredients:

Ingredient mg/Tablet Dextromethorphan Hydrobromide USP 40 Lactose NF 70Methocel E 15LV 100 Ethylcellulose NF 35 Magnesium Stearate NF 15Colloidal Silicon Dioxide NF 2

The embodiments and examples given above are illustrative of the presentinvention. Consequently it should be understood that modifications canbe made by those with ordinary skill in the art that are intended to becovered by the following claims.

1. A method of treating urinary incontinence which comprisesadministering to a mammal exhibiting urinary incontinence a urinaryincontinence alleviating amount of at least one morphinan selected fromthe group consisting of dextromethorphan, dextrorphan andpharmaceutically acceptable sahs thereof, in combination with apharmacologically active agent selected from the group consisting ofanticholinergics, sympathomimetics. tricyclic antidepressants,antispasmodics, direct-acting bladder smooth muscle relaxants,estrogens, compounds having estrogen-like activity, and any combinationof the foregoing.
 2. The method of claim 1 wherein the pharmacologicallyactive agent is selected from the group consisting of oxybutynin,atropine, propantheline, terodiline, dicyclomine, ephedrine,pseudoephedrine, phenylpropanolamine, amitriptyline, imipramine,doxepin, an estrogen and flavoxate.
 3. The method of claim 1 wherein themorphinan and pharmacologically active agent are contained in apharmaceutically acceptable vehicle.
 4. The method of claim 1 whereinthe morphinan and pharmacologically active agent are provided insustained release dosage form.
 5. The method of claim 1 wherein themorphinan and the pharmacologically active agent are administeredorally, intravenously, intramuscularly, subcutaneously, transdermally orintrathecally.
 6. A method of decreasing micturition frequency in amammal which comprises administering to a mammal a micturition frequencydecreasing amount of a morphinan selected from the group consisting ofdextromethorphan, dextrorphan and pharmaceutically acceptable saltsthereof, in combination with a pharmacologically active agent selectedfrom the group consisting of anticholinergics, sympathomimetics,tricyclic antidepressants, antispasmodics, direct-acting bladder smoothmuscle relaxants, estrogens, compounds having estrogen-like activity,and any combination of the foregoing.
 7. The method of claim 6 whereinthe pharmacologically active agent is selected from the group consistingof oxybutynin, atropine, propantheline, terodiline, dycydomine,ephedrine, pseudoephedrine, phenylpropanolamine, amitriptyline,imipramine, doxepin, an estrogen and flavoxate.
 8. The method of claim 6wherein the morphinan and pharmacologically active agent are containedin a pharmaceutically acceptable vehicle.
 9. The method of claim 6wherein the morphinan and pharmacologically active agent are provided insustained release dosage form.
 10. The method of claim 6 wherein themorphinan and the pharmacologically active agent are administeredorally, intravenously, intramuscularly, subcutaneously, transdermally orintrathecally.